Process of reacting mono- and di-saccharides with various reagents in the presence of gamma-butyrolactone



United States Patent PROCESS OF REACTING MONO- AND DI-SAC- CHARIDES WITHVARIOUS REAGENTS IN THE PRESENCE OF 'y-BUTYROLACTONE No Drawing. FiledMar. 4, 1958, Ser. No. 719,004 9 Claims. (Cl. 260209) This inventionrelates to a new process of reacting monosaccharides and disaccharideswith various reagents to yield a new class of compounds having utilityin various chemical industries.

From the various carbohydrates available only two have attained utilityin various chemical processing industries. Sorbitol,1,2,3,4,5,6-hexanehexol, has found use in pharmaceutical compounding, asa sugar substitute for diabetics, and in the manufacture of ascorbicacid, synthetic plasticizers, humectants, and the like. Mannitolobtained artificially by the reduction of mannose or fructose isemployed with boric acid in the manufacture of dry electrolyticcondensers for radio application, as a resin plasticizer, and in themanufacture of mannitol hexanitrate. There are many carbohydrates whichcould be used successfully for various applications, but for a lack ofsuitable synthesis to convert them to new and useful derivatives hasdiscouraged their exploitation on a commercial basis. For example, theinulin group of carbohydrates occurring in the tubers of the Jerusalemartichoke and in other members of the composite family of plants hasbeen hydrolyzed to fructose, a sugar 60% sweeter than sucrose, but therehas been no commercial production of the sugar itself or itsderivatives. Xylose which has been produced by the hydrolysis of xylanin cottonseed hulls has discouraged exploitation of the process due tothe failure to find important uses for this sugar by itself or in theform of various chemical derivatives.

Most of the monosaccharides and disaccharides are soluble in water. Someof them, while soluble in water, are also soluble or slightly soluble inalcohol. Many, however, are insoluble in alcohol and ether such as, forexample, fructose, glucose, and the like. Several monosaccharidesrequire solution in glacial acetic acid before they can be convertedinto sugar derivatives. The action of acetyl chloride or acetyl bromideon glucose, or the action of hydrobromic acid on pentaacetyl glucose inthe preparation of glucosides, requires the solution of the glucose inglacial acetic acid. In view of this shortcoming, it is impossible toprepare halide derivatives of the various carbohydrates because of thepartial esterification of the hydroxyl groups with acetic acid. Ifattempts are made to esterify the hydroxyl groups in carbohydrates withhalogen acids using dehydrating agents such as sulfuric acid or zincchloride, hydrolysis of the carbohydrates will take place first. This isdue to the fact that all carbohydrates such as pentose or hexose whenheated with mineral acids yield furfural and w-hydroxy-methyl furfuralrespectively. Sucrose in the presence of acids is hydrolyzed intod-glucose and d-fructose. Dilute mineral acids break down raffinose intofructose and melibiose. More powerful acid hydrolysis yields from eachmolecule of rafiinose, one molecule each of galactose,

glucose and fructose.

The difficulty in transforming the various monosaccharides anddisaccharides into new and useful derivatives is attributable to thefailure to find a suitable inert 2,938,898 Patented May 31, 1960 solventin which the polyhydroxy groups in the various carbohydrates would beamenable to reactivity with various chemical compounds. In the past suchreactions have been extremely difiicult, if not impossible, due to theinsolubility of the various carbohydrates in non-reactive non-aqueousmedia.

It is an object of the present invention to provide an improved processof preparing carbohydrate derivatives by employing 'y-butyrolactone inwhich the carbohydrates, i.e.'monosaccharides, fructose and glucose, andthe disaccharide, sucrose, are soluble and which are inert to a chemicalreagent reacting with one or more hydroxy groups in the carbohydratemolecule.

Other objects and advantages will become more clearly apparent from thefollowing description.

We have discovered that fructose, glucose and sucrose dissolved in'y-butyrolactone react readily with various reagents to give a varietyof new and useful compounds which are useful in the chemical andpharmaceutical industries. By the employment of 'y-butyrolactone asinert solvent-diluents, it is possible to react these specificcarbohydrates with acid anhydrides to give reaction prod ucts which aresoluble in ether. One or more hydroxyl groups of the carbohydrates canbe replaced by chlorine by means of phosphorus, triand pentachloride,the corresponding iodides and bromides by treatment with phosphorustri-iodide and phosphorus pentaiodide, and phosphorus tri-bromide andphosphorus pentabromide, re spectively. The resulting halogenderivatives can be employed for the preparation of a variety of estersby reacting the halide groups with potassium cyanide to yield nitriles.With potassium hydrogen sulfide, the halogen derivatives yield thioalcohols.

The carbohydrates, i.e. fructose, glucose and sucrose, in solution inthe 'y-butyrolactone may be subjected to alcoholysis by heating variousaliphatic and aromatic esters with the carbohydrates under conditions toinduce double decomposition in the presence of small amounts of acids.The carbohydrates in such solution may be esterified with variousinorganic and organic acids to yield monoand poly-esters. Nitrousanhydride may be employed to yield esters of nitrous acid. Variousesters of phosphoric acid may be prepared by the action of silverphosphate on the halide derivatives of the carbohydrates, or by theaction of phosphorus oxychloride on one or more hydroxyl groups of thecarbohydrates.

The most unusual feature of the present invention is that one or morehydroxyl hydrogens of the specific carbohydrates (fructose, glucose andsucrose) can be replaced by an alkali metal to yield the correspondingcarbohydralates. These are readily formed from alkali metals and thehydroxyl groups of the carbohydrate with evolution of hydrogen. Afterevaporation, the alkali metal alcoholate is left as an amorphous powder.The alkali metals such as sodium, potassium, and lithium are verysoluble in 'y-butyrolactone, and polyalcoholates are readily formed if acarbohydrate in 'y-butyrolactone is added to a solution of alkali metalin 'y-butyrolactone. Instead of distilling the solution to remove the'ybutyrolactone, the alcoholates can be precipitated out of solution bythe use of dioxane.

Since all halides and the alkali metal carbohydralates of theaforementioned specific carbohydrates are soluble in the'y-butyrolactone, this feature lends itself to the preparation ofvarious types of ethers. For example, monoand poly-alkali metalcarbohydralates may be made to react with one or more molecularequivalents of an alkyl halide such as, methyl iodide to yield monoandpoly-methyl ethers of the corresponding carbohydrates. The varioushalide esters of the carbohydrates may likewise be reacted with thealkali metal carbohydralates to yield a new variety of symmetrical andunsymmetrical-'ethers. The-halide derivatives of the variouscarbohydrates may amines. Amines may also be prepared by heating asolution of any carbohydrate in the pyrrolidone with zinc chloramine.

' z It'is'to' 'be'noted that thenature-or character of the reagent,which is' normally reactive-with one or more hydrogensof'hydroxyrgroups, is immaterialso long as \the reagent is soluble ordispersible in thebutyrolactone.

During the course of our experimentation. with the "'y-butyrolactoneas-inert-solventdiluents,'we have noted that all of thecurrently-available reagents-may be employed such as halogenhydracids;-e.g. hydrochloric acid, =hydrobromicracid, :hydroiodic' acid:and the like including 1 acids" such as nitrous acid, nitric" acid,hypochloric acid,

sulfuric a'cid, .'phosphoric acid, :boric acid, silicic 'acid,

unsaturated and saturated mono-iand. poIy-carboxylic acids andtheir-anhydrides I such cagafor.example," acetic acid, propionic acid,'butyric'aacid," zcaproicw acid,;capric 'acid, =acrylic acid, vinyl:acetic .acid,:methyl acrylicacid, =:-tei'acrylic acid, erucic acid, isorbic acid, amaleic 1 acid, f-umaric acid, adipic acid, sebacic 'acid,'citraconioacid, wtficarballylieacid, aconitic. acid, ethylene'tetracarboxylic be reacted with ammonia to yield acidl andzthe-like.-Acetylat1ng agents such as formyl chloride,:'; acetyl chloride,propionyllchloride, butyl chlo- *ride, stearoyl chloride,benzoyl'chlor-ideand the like, can also be employed-as the reagents toreact with one or more-zhydroxyl groups cf the "specific carbohydratesand -;their equivalents.

e Ast examples of the-specific l carbohydrates which 1 are soluble "inthe 'y-butyrolactones, and the resulting solutions subject to any one-0fthe J foregoing reactions, I the following are illustrative:

' D -glucose hydrate l-glucose hydrate Dl-glucose D-fructose--Dl-fructose -Sucrose The following "examples'will serve' to show howthe "processofour inventionmay be'carriedoutto yield a new .classofcarbohydrate "derivatives. It is tofbe understood'that theseexamplesaremerely illustrative'and are I not to-be construed asbeing limitative.

. Example! Example III "Example I was repeated except that 15.5 grams ofpolmitoyl chloride were used instead of 31.0 grams. The resultant solid(tetra-palmitoyl sucrose) in this case had essentially the same physicalproperties as in Example I except that it had a slightly higher meltingpoint.

' Example IV 1.0 gram of sucrose was added to 5.0 grams of'y-butyrolactone and the mixture heated until solution was complete. Theresulting solution is Water-soluble, but yields a white precipitate ofsucrose from carbon tetrachloride. To this solution were then added 5.0cc. of acetic anhydride and 0.1 gram of sodium methylate, and-themixture heated to the boil 'forseveral'minutes. The resulting solution,now straw colored and insoluble in water was soluble in carbontetrachloride. The resulting product is probably the tetra-acetate ofsucrose.

Example V One-tenth molecular equivalent ofd glucose (18.0162 grams) andsix-tenths molecular equivalent of'maleic anhydride (49.0300 grams)We're'added to 200cc. of v-butyrolactone and'heated under reflux for twohours. The reaction mixture was then drowned in two'liters ofwater,'andfiltered, then washed withwarm Water-,{Whrebyafdark brownsolution was obtained andnoprecipitate. This solution was'found to havegood foaming pro erties. 7

Example V1 1.0 gram; of sucrose was added to 5.0. grams of'y-butyrolactone and water soluble at the boil and white andWater-soluble'at room temperature. 3.0 cc. of sulfurylchloridewere ofwater, to. yield a heavy-brown precipitatewhich was filtered and washedwith warm water, andthen air'dried for forty-eight hours. Theresulting-darkbrown waxy -sol1d (octapalmitoyl sucrose) had alow-meltingpoint (less than 50 C.). Itrn'ay be employed as arelatively 1inexpensive plasticizer or inwater-rep'el'lent compositions.

Example II Example I was-repeated except that -5.0 ;igrarns of dfructosewere usedinsteadcf 5.0 grams oftsucrose. The-resultant solid-inthis case-had-essentialIy the-same rphysical properties as in ExarnpleI.

-d-glucose was substituted for 1.0 gram'of sucrose.

"added-and'an exothermic reaction occurred: giving ablacksolution,"which-on drowning in water gave no precipitate. The resultingcompound was identified -as a partially chlorinated sucrose.

Example VII 1.0 gram'of'sucrose was dissolved in 10.0 grams of"y-butyrolactone, and 1.0 gram of '1,4-dichloro-2-butyne was added andthe mixture heated for one-half hour.

. On drowning in water, no precipitate was obtained'and a yellowsolution results which has good foamingproperties. The resultingcompound'is believed to be a crosslinked carbohydrate containing severalgroups.

Example VIII Example V-II was'repea'ted except that 1.0 gramyof Thesolution also had good foaming resultant yellow properties.

Example IX To a '100 cc. flask, equipped with athermbmeter, stirrer andcondenser, 12.5 grams of sucrose, 3.31 grams of peanut oil,'0.046.gramof sodium-methylate, and 55.2 grams of 'y-butyrolactone were added andthe mixture heated with stirring for. 5 hours at 150-170 C. At the endof this time, a, portion-'- or the reaction mixture was drowned inwater. 'No precipitate forms and the yellow solution has foamingproperties. By partial evaporation and addition of sodium chloride,aprecipitate forms. This productfis water soluble'iand showsfoamingproperties. It can be employed as a foaming or sudsing agent.

'Exam'pl e X Example IX was repeated except*-that"12-.5 grams ofd-fructose-were added: instead of: 12.5 grams of sucrose.

he resultant propertieswere similar.

the mixture warmed until a: solu- :tion was obtained. The resultingsolution was clear and From the foregoing specification and workingexamples, it becomes clearly manifest that numerous reactions involvingone or more hydroxyl groups of the carbohydrates disclosed herein yieldnew derivatives having diversified uses in the chemical industry.

We claim:

1. The process of reacting at least one hydroxy group of a carbohydrateselected from the group consisting of fructose, glucose and sucrose witha reagent reactive with said group which comprises conducting thereaction in the presence of 'y-butyrolacetone in which the saidcarbohydrate and said reagent are soluble therein.

2. The process of reacting at least one hydroxy group of sucrose with areagent reactive with said group which comprises conducting the reactionin the presence of 7-butyrolactone in which the said sucrose and saidreagent are soluble therein.

3. The process of reacting at least one hydroxy group of fructose with areagent reactive with said group which comprises conducting the reactionin the presence of 'y-butyrolactone in which the said fructose and thesaid reagent are soluble therein.

4. The process of reacting at least one hydroxy group of glucose with areagent reactive with said group which comprises conducting the reactionin the presence of -butyrolactone in which the said glucose and the saidreagent are soluble therein.

5. The process of reacting at least one hydroxy group of sucrose withpalmitoyl chloride which comprises conducting the reaction in thepresence of 'y-butyrolactone 6 in which the said sucrose and the saidpalmitoyl chloride are soluble therein.

6. The process of reacting at least one hydroxy group of sucrose withacetic anhydride which comprises conducting the reaction in the presenceof 7-butyrolactone in which the said sucrose and the said aceticanhydride are soluble therein.

7. The process of reacting at least one hydroxy group of glucose withmaleic anhydride which comprises conducting the reaction in the presenceof 'y-butyrolactone in which the said glucose and the said maleicanhydride are soluble therein.

8. The process of reacting at least one hydroxy group of sucrose withsulfuryl chloride which comprises conducting the reaction in thepresence of 'y-butyrolactone in which the said sucrose and the saidsulfuryl chloride are soluble therein.

9. The process of reacting at least one hydroxy. group of sucrose with1,4-dichloro-2-butyne which comprises conducting the reaction in thepresence of 'y-butyrolactone in which the said sucrose and the said1,4-dichloro-2- butyne are soluble therein.

References Cited in the file of this patent UNITED STATES PATENTS2,602,789 Schwartz July 8, 1952 2,632,006 Blume Mar. 17, 1953 2,853,485Werner et a1 Sept. 23, 1958

1. THE PROCESS OF REACTING AT LEAST ONE HYDROXY GROUP OF A CARBOHYDRATESELECTED FROM THE GROUP CONSISTING OF FRUCTOSE, GLUCOSE AND SUCROSE WITHA REAGENT REACTIVE WITH SAID GROUP WHICH COMPRISES CONDUCTING THEREACTION IN THE PRESENCE OF V-BUTYROLACETONE IN WHICH THE SAIDCARBOHYDRATE AND SAID REAGENT ARE SOLUBLE THEREIN.